1. Field of the Invention
The present invention relates to photodynamic therapy and a method for preventing or reducing adverse effects during photodynamic therapy. In particular, the present invention relates to photodynamic therapy for age-related macular degeneration and tumors.
2. Description of the Related Art
Photodynamic therapy (PDT) is a treatment modality that is gradually entering clinical medicine. PDT is used to treat light-accessible localized tumors at sites where avoiding deforming surgery is a priority (McCaughan, 1984; Dougherty, 1984). PDT is also used in ophthalmology where it is an accepted treatment modality for causing occlusion of pathological microvessels emerging from the retinal choroid in the neovascular form of age related macular degeneration (Brown et al., 2001; Schmidt-Erfurth et al., 1999).
Age related macular degeneration (AMD) is a manifestation that occurs in elderly people, in which choroidal neovascularization (development of pathological blood vessels emerging from the choroid) is the major cause of blindness due to damage to the retinal pigmented epithelium and to the optic nerve (McLeod et al., 2000). These abnormal blood vessels cause apoptosis of the retinal pigmented epithelial (RPE) cells and consequently degeneration of neural retina photoreceptor cells. Since AMD is the primary cause of blindness in the elderly and constitutes a major cause of suffering and diminished quality of life, major efforts are directed to the treatment of AMD.
Current approaches to contain this problem have thus far focused on destroying these blood vessels by photodynamic therapy. The pathological vessel is photosensitized and irradiated with a concerted beam of laser light at wavelengths absorbed by the photosensitizer, i.e., argon laser at 689 nm with verteporfin as the photosensitizer. Reactive oxygen species such as singlet oxygen and free radicals are generated in this process and induce photodynamic damage (phototoxicity) to the endothelial cell layers that line the blood vessel, leading to ultimate destruction of the pathological vessel.
The sole photosensitizer that is approved for clinical use in photodynamic therapy of AMD is a benzoporphyrin derivative verteporfin known by its trade name VISUDYNE. This compound is a lipophilic reagent that attaches to low density lipoprotein (LDL) in the plasma and enters cells via the LDL receptor system. It has a visible range absorption peak at 689 nm, and a laser source is used in photosensitization.
A major disadvantage to this treatment modality is attributed to the pharmacokinetic properties of verteporfin (VISUDYNE), where there is a strict time-related limitation. Following intravenous administration, VISUDYNE remains in the intravascular compartment for only 30 minutes after which time it begins to disperse in the tissues. In the eye, the compound extravasates to the adjacent retinal pigmented epithelium (RPE), an ultra thin layer consisting of only 10 layers of cells. Laser therapy administered when VISUDYNE has spread to the RPE results in damage to the RPE, apoptosis (self-induced programmed cell death) of these cells and irreversible blindness. Clinicians, therefore, have a limited time frame of 20 minutes to no more than 30 minutes after intravenous administration of VISUDYNE to complete the laser portion of the treatment. Even within this limited time frame, the pathological nature of the vessel can, in many cases, lead to premature or accelerated leakage of the compound to the adjacent RPE and the laser treatment can result in severe adverse effects, such as extensive injury to the thin layer of macular RPE and vision impairment (Michels et al., 2002). As a result, ophthalmologists remain uneasy about performing these photodynamic treatments, and even when done, only the minimal number of treatments are applied resulting in low suboptimal cure rates.
In the absence of any other satisfactory treatment for AMD, ophthalmologists have been looking for ways to improve the level of RPE protection from phototoxicity and prevent collateral damage. These efforts focused on generating elevated levels of antioxidants in the RPE to neutralize cytotoxic reactive oxygen species resulting from photosensitization (Ochsner et al., 1997). However, obtaining high protective antioxidant concentrations in the RPE that will be selective and not include the endothelium of the choroidal vasculature targeted for destruction has yet to be achieved.
Hypericin is an aromatic polycyclic dione (perihydroxylated naphthodianthrone; dianthraquinone) compound which has previously been found to possess photodynamic properties (Duran et al., 1986 and Giese, 1980). It is lipophilic and has visible range light absorption peaks at 545 and 589 nm. The chemical structure of hypericin is shown in FIG. 1A. In the presence of light (and possibly other sources of energy), this compound excites oxygen to its singlet state and is capable of generating superoxide radicals which can lead, among other things, to oxidation of tryptophan imidazole groups in proteins and oxidation of fatty acids in biological systems.
Hypericin exhibits numerous potent biological activities, some of which have been found to occur in complete darkness. While inhibition of protein kinase C (Takahashi et al., 1989) and inhibition of MAP kinase activation (Agostinis et al., 1995) have been reported to be light dependent, recent unpublished work from the laboratory of the present inventor indicates that MAP kinase activation can occur in complete darkness. The present inventor and his colleagues have also investigated the use of hypericin and its quinone-containing analogs in the inactivation of retroviruses. See, for example, U.S. Pat. No. 5,047,435; Degar et al. (1991); Lavie et al. (1989); Lavie et al. (1989); Lavie et al. (1990); Lavie et al. (1991); Meruelo et al. (1988); Meruelo et al. (1991); Valentine et al. (1989); and Weiner et al. (1989). Hypericin is now considered as a potentially effective antiviral drug which can be used against a number of diseases caused by viruses.
Furthermore, hypericin has been found to cause (A) inhibition of cytotoxic T cell mediated cytotoxicity (U.S. Pat. No. 5,514,714 diseases) and can be used to inhibit T cell mediated diseases such as psoriasis; (B) anticancer activities in vivo against highly metastatic murine breast adenocarcinoma and anaplastic squamous cell carcinoma (U.S. Pat. Nos. 6,001,882 and 6,229,048 B1), and (C) inhibition of angiogenesis induced with heparanase or FGF-2 in the rat eye pocket model (U.S. Pat. No. 6,229,048 B1).
Citation of any document herein is not intended as an admission that such document is pertinent prior art, or considered material to the patentability of any claim of the present application. Any statement as to content or a date of any document is based on the information available to applicant at the time of filing and does not constitute an admission as to the correctness of such a statement.